Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer in the United States. Each year approximately one million new cases of NMSC are diagnosed in the United States with reported incidences increasing annually among the general population. Development of NMSC is primarily caused by repeated exposure to ultraviolet B (UVB) light from sun. Macrophage migration inhibitory factor (MIF) is a pleiotropi cytokine which is produced by variety of cells, including activated macrophages and neutrophils. Both of these cell types contribute to dermal inflammation induced by UVB light and have been implicated in the development of non-melanoma skin cancer (NMSC). MIF is an inducer of pro-inflammatory cytokines, a promoter of angiogenesis, a suppressor of p53 and has recently been re-discovered to act as a chemokine. Mounting evidence suggests that MIF serves as an important link between chronic inflammation and the development of cancer. Studies from our laboratory using MIF-/- BALB/c mice and by other investigators using MIF transgenic mice have found that MIF plays a critical role in induction of dermal inflammation and subsequent development of NMSC after UV light exposure. In recent preliminary studies, we have found that MIF mRNA levels are significantly increased in tumors of patients with squamous cell carcinoma (SCC) as well as in tumors that develop in hairless SKH-1 mice after UV exposure. These findings indicate that MIF is involved in the pathogenesis of acute UVB-induced skin inflammation as well as chronic UVB-induced NMSC development. The goals of this application are to test the hypotheses that MIF is a potential drug target in the chemoprevention and/or treatment of UVB-induced NMSC using a novel orally bio-available MIF antagonist. Aim 1 will determine whether blockade of MIF prevents acute UVB-induced dermal inflammation and subsequent tumor development in hairless SKH-1mice. Aim 2 will investigate whether MIF is a therapeutic target in treatment of established tumors in UV-exposed SKH-1 mice. Our team is uniquely poised to test this hypothesis and perform these studies due to complementary expertise in MIF/immunology/pathology (Satoskar), skin cancer (Oberyszyn) and MIF antagonists (Sielecki). Upon completion of these studies we will have determined whether MIF is a target in the prevention and treatment of NMSC, and whether small molecule MIF antagonists could be novel anti-cancer drugs. These data will lay the foundation for a latter RO1 application to develop better and safer MIF antagonists as novel drugs for prevention and treatment of skin cancer.